4marc.oa

The new england journal of medicine Alone, and the Two in Combination in Patients Patrick Marcellin, M.D., George K.K. Lau, M.D., Ferruccio Bonino, M.D., Patrizia Farci, M.D., Stephanos Hadziyannis, M.D., Rui Jin, M.D., Zhi-Meng Lu, M.D., Teerha Piratvisuth, M.D., Georgios Germanidis, M.D., Cihan Yurdaydin, M.D., Moises Diago, M.D., Selim Gurel, M.D., Ming-Yang Lai, M.D., Peter Button, M.Sc., and Nigel Pluck, M.D., for the Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group* b a c k g r o u n d
From the Service d’Hépatologie, INSERM Available treatments for hepatitis B e antigen (HBeAg)–negative chronic hepatitis B are Unité 481 and Centre de Recherches Claude associated with poor sustained responses. As a result, nucleoside and nucleotide ana- Bernard sur les Hépatites Virales, HôpitalBeaujon, Clichy, France (P.M.); Queen Mary logues are typically continued indefinitely, a strategy associated with the risk of resis- tance and unknown long-term safety implications.
Kong, China (G.K.K.L.); Istituto di Ricove-ro e Cura a Carratere Scientifico, Osped- ale Maggiore di Milano Policlinico, Milan, We compared the efficacy and safety of peginterferon alfa-2a (180 µg once weekly) plus Italy (F.B.); the Division of Clinical Medi-cine I, University of Cagliari, Cagliari, Italy placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively.
Patients were treated for 48 weeks and followed for an additional 24 weeks.
ens (S.H.); the Digestive Disease Depart-ment, Beijing You An Hospital, Beijing (R.J.);the Department of Infectious Diseases, Ruijin Hospital, Shanghai, China (Z.-M.L.); After 24 weeks of follow-up, the percentage of patients with normalization of alanine Songklanakarin Hospital, Songkla, Thailand aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per (T.P.); Papageorgiou General Hospital, Pa-thology Clinic, Thessalonika, Greece (G.G.); milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent University of Ankara, Faculty of Medicine, and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, Universitario de Valencia, Valencia, Spain(M.D.); University of Uludag, Faculty of respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with Taiwan University Hospital, Internal Med- peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent icine, Taipei, Taiwan (M.-Y.L.); Roche, DeeWhy, Australia (P.B.); and Roche, Welwyn, with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as com- pared with 0 patients in the group given lamivudine alone. Adverse events, including py- d’Hépatologie, INSERM Unité 481 and Cen-tre de Recherches Claude Bernard sur les rexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy Hépatites Virales, Hôpital Beaujon, 92110 than with peginterferon alfa-2a monotherapy or combination therapy. Clichy, France, or at patrick.marcellin@bjn.ap-hop-paris.fr.
c o n c l u s i o n s
Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of re- *Other members of the Peginterferon Alfa- sponse, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a Study Group are listed in the Appendix.
than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not im-prove post-therapy response rates.
N Engl J Med 2004;351:1206-17.
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Copyright 2004 Massachusetts Medical Society. All rights reserved.
p e g i n t e r f e r o n a l f a - 2 a in hbeag-negative chronic hepatitis b virus (HBV) is a major global health prob- lem, affecting more than 400 million peo- study design
ple worldwide.1 Chronic hepatitis B is associated This multicenter, randomized, partially double-with serious complications, including liver failure, blind study was conducted at 54 sites in 13 countries,cirrhosis, and hepatocellular carcinoma. Hepatitis principally in Asia and Europe. Patients were ran-B e antigen (HBeAg)–negative chronic hepatitis B domly assigned in a 1:1:1 ratio to receive 180 µg ofrepresents a late phase of the infection that is char- peginterferon alfa-2a (Pegasys, Roche) once weeklyacterized by progressive liver damage2,3 and viral plus oral placebo once daily, 180 µg of peginter-variants with changes in the precore or core promot- feron alfa-2a once weekly plus 100 mg of lamivu-er region,4,5 which abolish or suppress the expres- dine (Epivir-HBV or Zeffix, GlaxoSmithKline) oncesion of HBeAg. Spontaneous, sustained remissions daily, or 100 mg of lamivudine once daily. Random-are rare in HBeAg-negative chronic hepatitis B,6 ization was centralized and stratified accordingwhich has a poor prognosis. HBeAg-negative to geographic region and alanine aminotransfer-chronic hepatitis B occurs throughout the world, ase levels. The study, which comprised 48 weeksand its prevalence is increasing.4,6 of treatment followed by 24 weeks of follow-up, HBeAg-negative chronic hepatitis B responds was conducted according to the guidelines of the well to currently available therapies during treat- Declaration of Helsinki and the principles of Goodment. However, relapse rates are high after treat- Clinical Practice. All patients gave written informedment cessation, and the rates of sustained response consent.
are poor.7-10 Current consensus guidelines rec- The study was designed by the sponsor (Roche) ommend the use of interferon alfa or nucleoside in collaboration with expert hepatologists. Clinical
or nucleotide analogues as first-line therapy for data were collected by the Peginterferon Alfa-2a
HBeAg-negative chronic hepatitis B.6,11-13 How- HBeAg-Negative Chronic Hepatitis B Study Group.
ever, conventional interferon alfa has suboptimal The sponsor held the data and conducted the sta-
pharmacokinetics, necessitating an inconvenient tistical analyses; the principal authors had full ac-
dosing regimen. Lamivudine is associated with cess to the data and were actively involved in the
drug resistance, which increases with extended analysis and interpretation of the data and the draft-
use.14,15 Studies in patients with chronic hepatitis ing of the manuscript. All authors approved the fi-
B have produced conflicting results regarding the nal manuscript.
benefits of combining interferon alfa and lamivu-
dine,16-18 and the role of such combinations in the patients
treatment of chronic hepatitis B requires further Adult patients were eligible if they had been nega-
clarification.
tive for HBeAg and positive for anti-HBe antibody Peginterferon alfa-2a, created by attaching a and hepatitis B surface antigen (HBsAg) for at least large, branched, 40-kD polyethylene glycol mole- six months, had an HBV DNA level of more thancule to interferon alfa-2a,19 has better pharmaco- 100,000 copies per milliliter, had a serum alaninekinetics than conventional interferon alfa.20 This aminotransferase level that was greater than 1 butallows for convenient once-weekly dosing, with ef- less than or equal to 10 times the upper limit of thefective serum levels maintained throughout the normal range, and had had findings on a liver bi-dosing interval.20 Peginterferon alfa-2a, like con- opsy within the previous 24 months consistentventional interferon alfa, has a dual immunomod- with the presence of chronic hepatitis B, with evi-ulatory and antiviral mode of action but has yielded dence of prominent necroinflammatory activity (assuperior clinical outcomes in patients with chronic assessed by a local pathologist). Exclusion criteriahepatitis C21 and patients with HBeAg-positive included decompensated liver disease, a coexistingchronic hepatitis B.22 The current study was de- serious medical or psychiatric illness, a neutrophilsigned to assess the efficacy and safety of three count of less than 1500 per cubic millimeter, a plate-regimens in patients with HBeAg-negative chronic let count of less than 90,000 per cubic millimeter,hepatitis B: peginterferon alfa-2a monotherapy, a serum creatinine level that was more than 1.5peginterferon alfa-2a plus lamivudine, and lamivu- times the upper limit of the normal range, a historydine monotherapy.
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The new england journal of medicine try, treatment for chronic hepatitis B within the pre- resistance analysis
vious six months, and coinfection with hepatitis C At the end of treatment (week 48), HBV DNA was
virus (HCV) or hepatitis D virus or human immu- extracted from all available serum samples from
nodeficiency virus.
patients in the two lamivudine groups. Mutationsin the YMDD (tyrosine, methionine, aspartate, and e f f i c a c y m e a s u r e s
aspartate) motif of the HBV polymerase gene were Efficacy analyses included all randomized patients identified by means of the INNO-LiPA HBV DR as-
who received at least one dose of study medication. say (Innogenetics).24
The study had two predetermined primary mea-
sures of efficacy assessed after 24 weeks of follow- statistical analysis
up: the normalization of alanine aminotransferase A sample size of 160 patients per treatment group
levels and the suppression of HBV DNA levels to provided the study with a statistical power of 80
below 20,000 copies per milliliter. Alanine amino- percent at the 0.025 level of significance to detect
transferase was measured at local laboratories in a difference in response rates of 15 percent. The
accordance with standard procedures. Serum HBV sample size was increased to 175 patients to allow
DNA was measured at one of three central labo- for withdrawals. The goals of the study were con-
ratories with the use of the Cobas Amplicor HBV sidered to have been reached in the event of a sig-
Monitor Test (Roche Diagnostics).
nificant result for either primary efficacy outcome.
Secondary efficacy measures assessed after 24 Therefore, a significance level of 0.025 was cho- weeks of follow-up included the proportion of sen for the two primary efficacy measures to main-patients with HBsAg loss, HBsAg seroconversion tain the overall significance level at 0.05. For sec-(defined by the loss of HBsAg and the presence of ondary efficacy measures, the level of significanceanti-HBs antibody), histologic response, and sup- was set at 0.05.
pression of HBV DNA to below 400 copies per mil- The Cochran–Mantel–Haenszel test, stratified liliter. A histologic response was defined as a reduc- according to geographic region and pretreatmenttion of at least two points in the modified Histologic alanine aminotransferase level, was used to compareActivity Index score as compared with the pretreat- differences in response rates between the treatmentment score. Scores for this index can range from groups. Only if the overall test of the treatment ef-0 to 24, with inflammation graded from 0 (none) to fect was significant were pairwise comparisons per-18 (severe) and fibrosis graded from 0 (none) to formed. Fisher’s exact test was used when appro-6 (cirrhosis).23 Biopsy samples were scored by an priate. For each treatment group, response ratesindependent histopathologist who was unaware of were computed with their corresponding 95 percentthe timing of the biopsy or the patient’s treatment confidence intervals. No interim analyses were per-assignment. Ranked assessments of necroinflam- formed. Response rates were calculated for all pa-matory activity and fibrosis were also performed tients who received at least one dose of study drug,(and scored as improved, unchanged, or worse).
according to the intention-to-treat principle. Pa-tients with values missing at week 72 were classi- s a f e t y a n a l y s i s
Measures of safety included adverse events, hema-tologic measurements, clinical chemical measure- ments, and vital signs. Adverse events were graded
on a three-point scale (mild, moderate, and severe), characteristics of the patients
and causality was determined by the investigator. Of the 552 patients who underwent randomiza-
Safety was assessed at baseline; at weeks 1, 2, 4, 6, tion, 537 were included in the analyses. Five pa-
8, and 12 and every six weeks thereafter through- tients randomly assigned to receive peginterferon
out treatment; and every four weeks during fol- alfa-2a monotherapy, seven assigned to peginter-
low-up. Safety analyses included all randomized feron alfa-2a plus lamivudine, and three assigned
patients who received at least one dose of study med- to lamivudine monotherapy were excluded from
ication and who underwent at least one safety as- analyses — six did not receive study medication,
sessment after baseline.
and all nine patients from a single center were ex- Downloaded from www.nejm.org at ROCHE DIAGNOSTICS GMBH on September 16, 2004.
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p e g i n t e r f e r o n a l f a - 2 a in hbeag-negative chronic hepatitis b cluded owing to irregularities in study conduct. Of 72), the percentage of patients with normalized ala-the 537 patients included in the analyses, 26 receiv- nine aminotransferase levels was significantly high-ing lamivudine, 17 receiving peginterferon alfa-2a er with peginterferon alfa-2a monotherapy (59 per-plus lamivudine, and 12 receiving peginterferon cent) and peginterferon alfa-2a plus lamivudine (60alfa-2a monotherapy either did not complete treat- percent) than with lamivudine monotherapy (44ment or did not enter or complete follow-up. Base- percent; P=0.004 and P=0.003, respectively) (Ta-line demographic and other characteristics were ble 2 and Fig. 1A). The patterns of alanine amino-similar among the three treatment groups (Table 1). transferase levels throughout the study are shown in b i o c h e m i c a l r e s p o n s e
During therapy, marked elevations in alanine At the end of treatment (week 48), the proportion aminotransferase (more than 10 times the upperof patients with normalized alanine aminotrans- limit of the normal range, or more than 300 IU perferase levels was highest with lamivudine mono- liter) were observed in a significantly higher per-therapy (Table 2). After 24 weeks of follow-up (week centage of patients receiving peginterferon alfa-2a Table 1. Baseline Characteristics of the Patients.
Peginterferon
Peginterferon
Alfa-2a plus Placebo
Alfa-2a plus Lamivudine
Lamivudine
Characteristic
Bridging fibrosis or cirrhosis — no. (%)‡ * Race was generally assigned by the investigator but in rare instances was clarified with the patient. † The upper limit of the normal range is 30 IU per liter.
‡ The presence or absence of bridging fibrosis and cirrhosis was assessed by local pathologists.
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The new england journal of medicine Table 2. Rates of Biochemical, Virologic, and Histologic Response.*
Response
End of Treatment (Week 48)
End of Follow-up (Week 72)
Biochemical response
Normalization of alanine
Virologic response
HBV DNA <20,000 copies/ml§
Combined response
Normalization of alanine
aminotransferase and HBV DNA <20,000 copies/ml monotherapy (12 percent) than peginterferon alfa- highest with the combination regimen (Table 2).
2a plus lamivudine (4 percent) or lamivudine mono- At week 72, suppression of HBV DNA levels to be-therapy (6 percent; P=0.007 and P=0.038, respec- low 20,000 copies per milliliter occurred in a sig-tively). In contrast, the percentage of patients with nificantly higher percentage of patients receivingmarked elevations in alanine aminotransferase lev- peginterferon alfa-2a monotherapy (43 percent) orels after therapy was significantly higher with la- peginterferon alfa-2a plus lamivudine (44 percent)mivudine monotherapy (14 percent) or peginterfer- than lamivudine monotherapy (29 percent; P=0.007on alfa-2a plus lamivudine (15 percent) than with and P=0.003, respectively) (Table 2 and Fig. 1B).
peginterferon alfa-2a monotherapy (7 percent; P= Rates of suppression of HBV DNA to below 4000.03 and P=0.02, respectively). There was a sig- copies per milliliter at week 72 were 19 percent withnificant association between a marked elevation peginterferon alfa-2a monotherapy, 20 percent within alanine aminotransferase during therapy and peginterferon alfa-2a plus lamivudine, and 7 per-normalization of alanine aminotransferase levels cent with lamivudine alone (P<0.001 for both com-at week 72 (P=0.01).
After 48 weeks, the extent of suppression of v i r o l o g i c r e s p o n s e
HBV DNA from baseline was greatest with peginter- At week 48, the percentage of patients with HBV feron alfa-2a plus lamivudine (Table 2); the extentDNA levels below 20,000 copies per milliliter was of HBV DNA suppression was similar with peginter- Downloaded from www.nejm.org at ROCHE DIAGNOSTICS GMBH on September 16, 2004.
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p e g i n t e r f e r o n a l f a - 2 a in hbeag-negative chronic hepatitis b Table 2. (Continued.)
Response
End of Treatment (Week 48)
End of Follow-up (Week 72)
aminotransferase and HBV DNA <400 copies/ml Histologic response¶
No. of patients¿
Ranked assessments of
histologic response††
Fibrosis
Total no. of patients
* All P values are from the Cochran–Mantel–Haenszel test for the pairwise comparison of each peginterferon alfa-2a group with the lamivu- dine monotherapy group at week 72. CI denotes confidence interval.
† P=0.003 for the overall test of treatment effect.
‡ Odds ratios are given with 95 percent confidence intervals only for the two primary efficacy outcomes.
§ P=0.005 for the overall test of treatment effect.
¶ Histologic response was defined as a reduction of at least two points in the modified Histologic Activity Index score, as compared with the pretreatment score, according to criteria of Ishak et al.23 ¿ Patients without paired biopsy samples were classified as having no response. P=0.144 for the overall test of treatment effect.
** Patients without paired biopsy samples were excluded. P=0.101 for the overall test of treatment effect.
†† Ranked assessments included patients with assessable liver-biopsy specimens at baseline and at week 72. “Improved” and “worse” were de- fined as a reduction of at least two points and an increase of at least two points in the modified Histologic Activity Index score, respectively.
feron alfa-2a monotherapy and lamivudine mono- and three receiving the combination regimen. Attherapy. The patterns of HBV DNA levels through- week 72, HBsAg loss or seroconversion was notout the study are shown in Figure 2B.
identified in any patients receiving lamivudinemonotherapy. Differences in HBsAg loss and se- h b sag response
roconversion between peginterferon alfa-2a mono- At week 72, HBsAg loss occurred in seven pa- therapy and lamivudine monotherapy were signif-
tients receiving peginterferon alfa-2a monothera- icant (P=0.007 and P=0.029, respectively, by Fisher’s
py (five Asian and two white patients) and in five exact test).
receiving peginterferon alfa-2a plus lamivudine
(four and one, respectively). HBsAg seroconver- histologic response
sion (defined by the loss of HBsAg and the pres- The rate of histologic response was similar among
ence of anti-HBs antibody) occurred in five pa- the three treatment groups (Table 2). There was a
tients receiving peginterferon alfa-2a monotherapy significant association between improved histo-
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The new england journal of medicine r e s i s t a n c e
At week 48, YMDD mutations were detected in 32 of 179 patients receiving lamivudine monother- apy (18 percent) and 1 of 173 patients receiving peginterferon alfa-2a plus lamivudine (1 percent, P<0.001 by Fisher’s exact test).
The rate of withdrawal from therapy was low in allthree groups (Table 3). The rates of adverse events were similar in the peginterferon alfa-2a and com- Biochemical Response (%)
bination-therapy groups but were significantly less frequent in the lamivudine group. The most com- mon adverse events were those known to occur with Peginterferon Alfa-2a
Peginterferon Alfa-2a
Lamivudine
plus Placebo
plus Lamivudine
conventional interferon alfa therapy, including py-rexia, fatigue, myalgia, and headache (Table 3).
Depression was infrequent during the study and was reported by six patients (3 percent) receivingpeginterferon alfa-2a monotherapy, eight patients (4 percent) receiving peginterferon alfa-2a plus la- mivudine, and two patients (1 percent) receivinglamivudine monotherapy. Twenty-six patients had a total of 27 serious adverse events: 9 (5 percent) patients receiving peginterferon alfa-2a monotherapy, 12 patients Virologic Response (%)
(7 percent) receiving peginterferon alfa-2a pluslamivudine, and 5 patients (3 percent) receiving la- mivudine monotherapy (Table 3). Nine patients had serious infections; however, the incidence was sim- Peginterferon Alfa-2a
Peginterferon Alfa-2a
Lamivudine
plus Placebo
plus Lamivudine
ilar in each treatment group (1 to 2 percent). Therewere two cases of serious thyroid disorders in the Figure 1. Rates of Biochemical Response (Panel A) and Virologic Response
peginterferon alfa-2a group. All other serious ad- (Panel B) after 24 Weeks of Follow-up.
verse events were single cases in a variety of body A biochemical response was defined as the normalization of alanine amino- systems. Hepatic decompensation was not report- transferase levels. A virologic response was defined as an HBV DNA level of ed in any patient during the study period, even less than 20,000 copies per milliliter. Differences were assessed by means of though 27 percent of patients had bridging fibro- the Cochran–Mantel–Haenszel test, stratified according to geographic region and pretreatment alanine aminotransferase level. The number of patients in sis or cirrhosis on pretreatment liver biopsy.
each group is shown in each bar, and the percentage of patients with a response Mean neutrophil and platelet counts were re- in each group is shown above each bar.
duced during treatment with peginterferon alfa-2amonotherapy and peginterferon alfa-2a plus lamiv-udine, yet returned to baseline levels shortly aftertreatment was stopped. Neutropenia and throm- logic activity and either a biochemical or virologic bocytopenia were the most common reasons forresponse at week 72, regardless of the treatment dose modification (Table 3).
group (P<0.001). A histologic response occurredin 151 of 292 patients with a biochemical response (52 percent), as compared with 70 of 245 patientswithout a biochemical response (29 percent). A his- We found that peginterferon alfa-2a alone or intologic response was seen in 116 of 208 patients combination with lamivudine resulted in higherwith a virologic response (56 percent), as com- rates of sustained response among patients withpared with 105 of 329 patients without a virologic HBeAg-negative chronic hepatitis B than did lamiv-response (32 percent).
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p e g i n t e r f e r o n a l f a - 2 a in hbeag-negative chronic hepatitis b Serum Alanine Aminotransferase (IU/liter)
No. of patients
Peginterferon alfa-2a plus placebo
Mean HBV DNA (log copies/ml)
No. of patients
Peginterferon alfa-2a plus placebo
Figure 2. Mean Serum Alanine Aminotransferase Levels (Panel A) and HBV DNA Levels (Panel B) during the 72-Week
Study Period.
tion of alanine aminotransferase levels, suppres- 20,000 copies per milliliter after 24 weeks of fol-sion of HBV DNA, and the loss or seroconversion low-up. This sustained suppression of HBV DNAof HBsAg. Previous studies have suggested that (perhaps in combination with normalized alaninelow levels of viremia may be compatible with the aminotransferase levels) might reduce the risk ofpresence of minimally active hepatitis B.12,25,26 In end-stage liver disease or hepatocellular carcinoma.
this study, over 40 percent of patients receiving Longer follow-up is necessary to clarify the long-peginterferon alfa-2a had HBV DNA levels below term benefits of peginterferon alfa-2a therapy.
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The new england journal of medicine Table 3. Incidence of Discontinuation of Treatment, Dose Modification, and Adverse Events.*
Peginterferon Alfa-2a
Peginterferon Alfa-2a
plus Placebo
plus Lamivudine
Lamivudine
Variable
Discontinuation
Dose modification§
Adverse events
* Values are based on all randomized patients who received at least one dose of study medication and who underwent at least one safety assessment after baseline.
† P<0.001 for the overall test of treatment effect.
‡ P=0.913 for the overall test of treatment effect.
§ Some patients who required a dose modification had both an adverse event and a laboratory abnormality.
¶ A serious adverse event was one that presented a clinically significant hazard or resulted in a contraindication or side ¿ Thrombotic thrombocytopenic purpura developed in this patient.
** Patients may have had more than one adverse event. The adverse events listed are those reported by at least 5 percent of patients in one of the peginterferon alfa-2a groups up to eight weeks after therapy.
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p e g i n t e r f e r o n a l f a - 2 a in hbeag-negative chronic hepatitis b In patients with HBeAg-positive chronic hepati- difference indicates that a more profound HBV tis B, alanine aminotransferase flares during thera- DNA suppression, as seen during treatment withpy with interferon alfa have been indicated as a peginterferon alfa-2a in combination with lamivu-significant predictor of response.27 However, this dine, may lead to a lower incidence of lamivudineassociation is less clear in patients with HBeAg- resistance. This finding concurs with general theo-negative chronic hepatitis B. The identification of a ries on the development of antiviral drug resistancesignificant association between alanine amino- and confirms data reported in other studies oftransferase flares during treatment and response HBV.32 Longer follow-up of patients in this studyin this study indicate that alanine aminotransferase may clarify any additional benefits of combinationflares may also be predictive of response in these therapy in the treatment of chronic hepatitis B.
patients.
The tolerability and safety profiles of peginter- HBsAg loss or seroconversion after therapy is feron alfa-2a alone and in combination with lamiv- considered the ultimate therapeutic goal of anti- udine were satisfactory, and there were no unex-HBV therapy, since it is associated with positive pected adverse effects. Moreover, the addition oflong-term clinical outcomes.6,12,28 In this study, lamivudine did not substantially alter the safetyHBsAg loss was identified in 12 patients receiving profile of peginterferon alfa-2a. The safety profilepeginterferon alfa-2a alone or in combination with of peginterferon alfa-2a also compares favorablylamivudine, 8 of whom underwent HBsAg sero- with the profiles described in previous studies ofconversion by the end of 24 weeks of follow-up, as conventional interferon alfa in patients with HBeAg-compared with none receiving lamivudine alone. negative chronic hepatitis B.7,33 It is noteworthyThis observation concurs with those of previous that no patient, including those with bridging fi-studies showing that interferon alfa therapy is as- brosis or cirrhosis, had hepatic decompensationsociated with an HBsAg response in patients with during either treatment or follow-up.
HBeAg-negative chronic hepatitis B.29 However, the The incidence of depression with peginterferon HBsAg response elicited by conventional interfer- alfa-2a in this study (3 to 4 percent) was lower thanon alfa tends to occur later than that observed with previously observed among patients with chronicpeginterferon alfa-2a in this study.7,10,28 HBsAg hepatitis C (16 to 20 percent).21,34 This findingloss or seroconversion was not reported in several concurs with previous data showing that the rate ofclinical trials of lamivudine or adefovir in patients depression is lower among patients with chronicwith HBeAg-negative chronic hepatitis B.8,9,15,30 hepatitis B than among patients with chronic hep-These results illustrate the importance of the dual atitis C, both at baseline and during interferon alfaimmunomodulatory and antiviral effects of inter- therapy.35 The reasons for this remain unclear;feron-based therapies in the treatment of HBeAg- however, virus-specific factors (e.g., HCV infectionnegative chronic hepatitis B.
of the central nervous system) and host-suscepti- No significant differences in efficacy were ob- bility factors (e.g., the patient population and the served between the peginterferon alfa-2a mono- presence of preexisting psychiatric disorders) maytherapy and combination groups after 24 weeks influence the rates of depression.35,36of follow-up. This finding extends those of other The results of this large, multinational study recent studies. For example, Santantonio and co- demonstrate that peginterferon alfa-2a offers sig-workers showed that adding conventional inter- nificantly improved efficacy over lamivudine in theferon alfa to lamivudine therapy did not increase treatment of HBeAg-negative chronic hepatitis B.
response rates in patients with HBeAg-negative The ability of this agent to improve and sustain bio-chronic hepatitis B when assessed 24 weeks after chemical, virologic, and HBsAg response rates con-the end of treatment.18 Similarly, recent prelimi- stitutes a therapeutic advance over current treat-nary data have suggested that after 24 weeks of fol- ments, which are associated with poor rates oflow-up, the combination of peginterferon alfa-2b sustained response after the cessation of therapy.
and lamivudine is no more effective than peginter- Our data demonstrate the possibility of achievingferon alfa-2b monotherapy in patients with HBeAg- HBsAg loss or seroconversion in patients withpositive chronic hepatitis B.31 HBeAg-negative chronic hepatitis B with the use of Significantly fewer patients receiving combi- peginterferon alfa-2a and therefore support the use nation therapy than lamivudine monotherapy had of this agent as a first-line therapy for HBeAg-neg-YMDD mutations at the end of treatment. This ative chronic hepatitis B.
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The new england journal of medicine Supported by a research grant from Roche, Basel, Switzerland.
and as a consultant for Bristol-Myers Squibb; Dr. Diago as a con- Mr. Button and Dr. Pluck are employees of Roche. Dr. Marcellin re- sultant for Roche and a lecturer for Roche, Schering-Plough, and ports having served as a consultant for Roche, Bristol-Myers Squibb, GlaxoSmithKline; and Drs. Lau, Bonino, and Piratvisuth as consul- Gilead Sciences, Bayer, Novartis, Vertex Pharmaceuticals, and Valeant Pharmaceuticals and as a lecturer for Roche, Bristol-Myers Squibb, We are indebted to Dr. Friederike Zahm and Dr. Matei Popescu of Gilead Sciences, Schering-Plough, and GlaxoSmithKline; Dr. Hadziy- Roche, Basel, Switzerland; Dr. Philip McCloud of Roche, Dee Why, annis as a consultant and lecturer for Roche, Bristol-Myers Squibb, Australia; and Dr. Martyn Corbey of Roche, United Kingdom, for Gilead Sciences, Schering-Plough, and GlaxoSmithKline; Dr. Yur- their critical analysis of the study data.
daydin as a consultant and lecturer for Roche and Gilead Sciences a p p e n d i x
In addition to the authors, the Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group includes the following persons: J.
Aguilar Reina (Hospital Virgen Del Rocio, Seville, Spain); H. Akkiz (University of Cukurova, Balcali-Adana, Turkey); T. Berg (Charité Uni-versity Hospital, Berlin); M.R. Brunetto (Hepatology Unit, Cisanello Hospital, Pisa, Italy); G. Cadeo (Civil Hospital, Brescia, Italy); Y.-C.
Chao (Tri-Service General Hospital, Taipei, Taiwan); T.-N. Chau (Princess Margaret Hospital, Kowloon, Hong Kong, China); A. Chutaputti(Pramongkutklao Hospital, Bangkok, Thailand); E. Gane (Middlemore Hospital, Auckland, New Zealand); T. Goeser (University Hospital,Cologne, Germany); W. Halota (Hospital for Infectious Diseases, Bydgoszcz, Poland); A. Horban (Hospital for Infectious Diseases, War-saw, Poland); J.-D. Jia (Beijing Friendship Hospital, Liver Research Centre, Beijing); M.-C. Jung (University Clinic, Grosshadern, Munich,Germany); S. Kaymakoglu (University of Istanbul, Istanbul Medical Faculty, Istanbul, Turkey); G. Kittis (Georgios Papanikolaou Hospital,Thessaloniki, Greece); J. Kuydowicz (Medical University of Lodz, Lodz, Poland); S.-D. Lee (Taipei Veterans General Hospital, Taipei, Tai-wan); B.-J. Lei (First Affiliated Hospital, Western China Medical University, Chengdu, China); K.-X. Luo (Nangfong Hospital, Guang-zhou, China); V. Mahachai (Chulalongkorn Hospital, Bangkok, Thailand); G. Minuk (Health Science Centre, Winnipeg, Ont., Canada);G. Pastore (Clinic of Infectious Diseases, University of Bari, Bari, Italy); D. Prokopowicz (Medical University of Bialystok, Bialystok, Po-land); J.W.F. Rasenack (University Hospital, Freiburg, Germany); J. Reichen (University Hospital, Berne, Switzerland); L. Sik (PrincessMargaret Hospital, Hong Kong); T. Tanwandee (Siriraj Hospital, Bangkok, Thailand); S. Thongsawat (Chiang Mai University, ChiangMai, Thailand); N. Tozun (University of Marmara, Faculty of Medicine, Istanbul, Turkey); C. Trepo (Hotel Dieu, Lyon, France); E. Tsianos(University Hospital of Ionnina, Ionnina, Greece); M.-B. Wan (Changhai Hospital, Shanghai, China); H. Wang (People’s Hospital of PekingUniversity, Beijing); Q.-H. Wang (First Affiliated Hospital of Peking University, Beijing); D.-Z. Xu (Beijing Ditan Hospital, Beijing); G. Yao(Shanghai Jing An Central Hospital, Shanghai, China); J.-L. Yao (Third Affiliated Hospital of Sun Yat-Sen, Medical Science University,Guangzhou, Guangdong, China); Y.-S. Yu (First Affiliated Hospital, College of Medical Science, Zheijiang University, Hangzhou, China); S.
Zeuzem (J.W. Goethe University Hospital, Frankfurt, Germany); D. Zhang (Second Affiliated Hospital, Chongqing Medical College, Chong-qing, China); H.-F. Zhang (Beijing 302 Hospital, Beijing); and Q.-B. Zhang (Huashan Hospital, Shanghai, China).
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